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Heat shock protein 90 inhibitors overcome chemoradiotherapy resistance conferred by erbB2 and NFκB overexpression in muscle-invasive bladder cancer

Research Project

Project/Area Number 19791103
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field Urology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

YOSHIDA Sochiro  Tokyo Medical and Dental University, 医学部・附属病院, 医員 (80383280)

Project Period (FY) 2007 – 2009
Project Status Completed (Fiscal Year 2009)
Budget Amount *help
¥3,810,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥510,000)
Fiscal Year 2009: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywords浸潤性膀胱癌 / 化学放射線療法 / anti-apoptotic protein
Research Abstract

Improvement of response of bladder cancer to chemoradiotherapy is expected not only to provide the patients a chance of bladder preservation but to improve their survival outcomes. We identified key molecules responsible for chemoradiotherapy resistance in clinical cohort. In the patients with muscle bladder cancer underwent radiotherapy plus concomitant cisplatin at low-dose (low-dose chemoradiotherapy, LCRT) as an induction therapy prior to curative surgery, overexpression of erbB2 and nuclear NFκB p65 in transurethral biopsy specimens obtained prior to LCRT significantly and independently associates with LCRT resistance. Destabilizing erbB2 and inhibiting nuclear translocation of NFκB by using Heat shock protein 90 (Hsp90) inhibitor; 17-DMAG, sensitizes bladder cancer cell lines (T24, UM-UC-3 and 5637) to in vitro LCRT by enhancing apoptosis. This sensitizing effect was not observed in primarily cultured normal human urothelial (NHU) cells. Pretreatment with Hsp90 inhibitor; 17-AAG, successfully overcame in vivo LCRT resistance of human bladder cancer xenograft of UM-UC-3 bladder cancer cells overexpressing erbB2 and NFκB. Hsp90 inhibitors, simultaneously abrogating erbB2 and NFκB pathways, tumor-selectively sensitize bladder cancer cells to LCRT and overcome LCRT resistance in preclinical models.These results encourage clinical trials of Hsp90 inhibitors adjunct to chemoradiotherapy to improve oncological outcomes and QOL in patients with muscle bladder cancer.

Report

(4 results)
  • 2009 Annual Research Report   Final Research Report ( PDF )
  • 2008 Annual Research Report
  • 2007 Annual Research Report
  • Research Products

    (15 results)

All 2010 2009 2008 Other

All Journal Article (5 results) (of which Peer Reviewed: 1 results) Presentation (5 results) Remarks (5 results)

  • [Journal Article] Initial Experience of Diffusion-weighted Magnetic Resonance Imaging to Assess Therapeutic Response to Induction Chemoradiotherapy against Muscle-invasive Bladder Cancer.2010

    • Author(s)
      Yoshida S, et al.
    • Journal Title

      Urology 75

      Pages: 387-91

    • Related Report
      2009 Final Research Report
  • [Journal Article] Initial experience of diffusion-weighted magnetic resonance imaging to assess therapeutic response to induction chemoradiotherapy against muscle-invasive bladder cancer2010

    • Author(s)
      Yoshida S
    • Journal Title

      Urology 75

      Pages: 387-391

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Initial experience of functional imaging of upper urinary tract neoplasm by diffusion-weighted magnetic resonance imaging.2008

    • Author(s)
      Yoshida S, et al.
    • Journal Title

      Int J Urol. 15

      Pages: 140-3

    • Related Report
      2009 Final Research Report
  • [Journal Article] C-reactive protein level predicts prognosis in patients with muscle-invasive bladder cancer treated with chemoradiotherapy.2008

    • Author(s)
      Yoshida S, et al.
    • Journal Title

      BJU Int. 101

      Pages: 978-81

    • Related Report
      2009 Final Research Report
  • [Journal Article] Female urethral diverticular abscess clearly depicted by diffusion-weighted magnetic resonance imaging.2008

    • Author(s)
      Yoshida S, et al.
    • Journal Title

      Int J Urol. 15

      Pages: 460-1

    • Related Report
      2009 Final Research Report
  • [Presentation] 浸潤性膀胱癌に対する化学放射線療法のMRIによる治療効果判定:拡散強調画像の有用性2010

    • Author(s)
      吉田宗一郎, 他
    • Organizer
      第98回日本泌尿器科学会総会
    • Place of Presentation
      岩手
    • Year and Date
      2010-04-30
    • Related Report
      2009 Final Research Report
  • [Presentation] Diffusion-weighted magnetic resonance imaging in diagnosis of upper urinary tract cancer.2010

    • Author(s)
      Yoshida S, et al.
    • Organizer
      5th Anniversary EAU Congress
    • Place of Presentation
      Barcelona, Spain, Abs.
    • Related Report
      2009 Final Research Report
  • [Presentation] Multi-sequence magnetic resonance imaging prior to prostate biopsy : Correlation analysis using the pathological results of three-dimensional 26-core(3D26) biopsy2009

    • Author(s)
      Yoshida S
    • Organizer
      24th annual European Association of Urology congress
    • Place of Presentation
      Stockholm
    • Year and Date
      2009-03-20
    • Related Report
      2009 Annual Research Report
  • [Presentation] Multi-sequence magnetic resonance imaging prior to prostate biopsy: Correlation analysis using the pathological results of three-dimensional 26-core (3D26) biopsy.2009

    • Author(s)
      Yoshida S, et al.
    • Organizer
      24th annual EAU congress
    • Place of Presentation
      Stockholm, Abs.
    • Related Report
      2009 Final Research Report
  • [Presentation] Functional imaging of upper urinary tract neoplasm by diffusion-weighted MRI.2008

    • Author(s)
      Yoshida S, et al.
    • Organizer
      23th annual EAU congress
    • Place of Presentation
      Milan
    • Year and Date
      2008-03-26
    • Related Report
      2009 Final Research Report
  • [Remarks] ホームページ:

    • URL

      http://www.tmd.ac.jp/med/uro/

    • Related Report
      2009 Final Research Report
  • [Remarks] 受賞:

    • Related Report
      2009 Final Research Report
  • [Remarks] (1) Yoshida S, et al. Diffusion-weighted magnetic resonance imaging in diagnosis of upper urinary tract cancer. Prize for the Third Best Abstract (Oncology). Awarded by European Association of Urology, 2010 at 25^<th> Anniversary EAU Congress, Barcelona, Spain, 16-20 April 2010.

    • Related Report
      2009 Final Research Report
  • [Remarks] (2) Yoshida S, et al. Best poster presentation award in Poster Session 2: Diffusion-weighted magnetic resonance imaging in diagnosis of upper urinary tract cancer. Awarded by European Association of Urology, 2010.

    • Related Report
      2009 Final Research Report
  • [Remarks] (3) Koga F, Kawakami S, Yoshida S, et al. Best poster presentation award in Poster Session 61: Treatment of advanced stage bladder cancer. Awarded by European Association of Urology, 2008.

    • Related Report
      2009 Final Research Report

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Published: 2007-04-01   Modified: 2021-04-07  

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